Adrenoleukodystrophy

There are multiple ways X-linked adrenoleukodystrophy can be expressed. These can be divided based on the symptoms that are present in any one particular patient. Childhood cerebral forms have an onset of ages 4-8 and symptoms include attention problems, poor school performance, difficulty in understanding speech, reading comprehension problems, clumsiness, and problems with eyesight. Children with this form may also have seizures and problems progress over time. The adrenomyeloneuropathy (AMN) form has symptoms often beginning in 20s-40s and symptoms include leg weakness, difficulties with digestion and sexual dysfunction that gets worse with time. Individuals with the Addison-disease-only type typically start showing symptoms in childhood that may include vomiting, weakness and changes in skin coloring. These problems can be helped with hormone replacement therapy.

Additional differences in presentation are seen in about 5-10% of individuals and symptoms include headache, behavior problems, memory loss, clumsiness, and/or bladder and bowel dysfunction.

Most commonly females will not typically show the full spectrum symptoms seen in males with an X-linked adrenoleukodystrophy diagnosis. About 20% of female carriers can experience some degree of numbness/tingling in their lower limbs or difficulty walking later in life. Symptoms in females usually resemble the adrenomyeloneuropathy type of adrenoleukodystrophy.

The first symptoms noticed by an individual with adrenoleukodystrophy will vary depending on what type of the disorder they have. In the childhood cerebral type, often early symptoms appear similar to ADD and many boys are first evaluated due to problems in school.

In the adrenomyeloneuropathy type, the first symptoms are often numbness or tingling in the feet and legs and stiffness or weakness in the feet and legs that can cause difficulty walking. Changes in bowel control and sexual function are also seen in this type.

In the Addison-disease-only type, the first symptoms are related to the adrenal glands not working properly. These symptoms include unexplained vomitting, weakness, or even coma. This type can present in childhood or adulthood, but often presents by 7.5 years of age.

Many of the symptoms seen in adrenoleukodystrophy are also present in other disorders. Most notably, one of the earliest sign of adrenoleukodystrophy is difficulty with attention, which may lead to a diagnosis of attention deficit disorder (ADD). Attention deficit disorder has many causes, and the vast majority of cases are unrelated to adrenoleukodystrophy. Seizures can also present in adrenoleukodystrophy, but there are many causes for seizures, as well. Other leukodystrophies, such as Krabbe disease or metachromatic leukodystrophy, may also have similar symptoms to childhood cerebral X-linked adrenoleukodystrophy.

The adrenomyeloneuropathy form of adrenoleukodystrophy, which often presents with muscle weakness and tingling in the feet and legs, may look like multiple sclerosis or amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). Other symptoms have overlap with Alzheimer disease, psychosis, brain tumors, and other conditions.

An individual showing the signs of adrenal insufficiency may be diagnosed with Addison's disease. Adrenoleukodystrophy is the most common genetic cause of Addison's disease, but most cases of Addison's disease are not caused by adrenoleukodystrophy. Addison's disease is often related to autoimmune disorders, infections, and can also be triggered by environmental factors, such as stopping corticosteroid medication, or changes to the pituitary gland in the brain.

Because of this overlap in symptoms, individuals with adrenoleukodystrophy may go through a "diagnostic odyssey" before they are correctly diagnosed.

While no single symptom is characteristic of X-linked adrenoleukodystrophy, certain combinations of symptoms can prompt further evaluation. For example, young boys showing signs of attention deficit disorder (ADD) and also problems with memory, abnormal behaviors, vision loss, and/or worsening clumsiness may need additional testing. Men in their 20s-30s with worsening muscle stiffness and problems with bowel control or sexual function should consider evaluation for adrenomyeloneuropathy. In addition, males who have adrenocortical insufficiency or are diagnosed with Addison's disease without an identified cause should consider further workup.

Medical evaluations are the best tools to recognize X-linked adrenoleukodystrophy. If the cerebral form is present MRI findings can be very characteristic. Blood testing that shows an abnormally high amount of very long chain fatty acids is also a sign of X-linked adrenoleukodystrophy.

Variable expressivity refers to the types of symptoms a disorder presents with, and if there is variation from one person with the disease to another. There is definitely variable expressivity in adrenoleukodystrophy, as people with the same changes to their ABCD1 gene can have very different symptoms. Even within the same family, different individuals may present with different forms of the disease.

Penetrance refers to whether all people with the genetic change will have the disease or not. Although there is a great deal of variable expressivity in adrenoleukodystrophy, 100% of males with a disease-causing ABCD1 mutation will have elevated levels of very long chain fatty acids in their blood. Additionally, although some males may appear to be asymptomatic, nearly all affected males will show neurological symptoms by adulthood.

ABCD1 is not a predisposition gene. Mutations in this gene are considered causative of X-linked adrenoleukodystrophy. It is not possible to predict which symptoms a male will show, nor is it possible to know in advance which female carriers will demonstrate some symptoms. In May 2019 a small study of individuals with childhood-onset X-linked adrenoleukodystrophy who also have a genetic variant called APOE4 may be at increased risk for more severe disease. However, this study requires further follow-up to determine if APOE4 is in fact adversely affecting the severity of X-linked adrenoleukodystrophy.